Chaperone behaviour in Parkinson's
PD is a degenerative disorder of the central nervous system and is the result of a lack of dopamine-generating cells in the substantia nigra in the mid-brain. Accumulation of a protein, alpha-synuclein (a-syn), that ultimately forms into aggregates known as Lewy bodies in neurons characterises the disease. Recent research has revealed that molecular chaperones such as heat shock protein Hsp104 are associated with the aggregation. However, details regarding how Hsp104 can be protective against a-syn toxicity and how it interacts with a-syn on a molecular level are so far unknown. The project 'The role of molecular chaperones in Parkinson' s Disease' (Chaperones IN ND) aimed to unravel the mechanisms by which molecular chaperones react with a-syn. Particularly important from a pathological point of view is how these proteins can prevent or revert a-syn amyloid formation and how they modulate structure and aggregation. To study a-syn interaction with Hsp104, project scientists produced recombinant characterised proteins. Assays for amyloids were also developed. To assess the role of adenosine triphosphate (ATP), ATPase enzyme assays were performed. Fluorescent dyes were used as molecular tags to study protein-protein interactions. Chaperones IN ND found that Hsp104 inhibits amyloid formation in a dose-dependent manner as it blocks the seeding of smaller units, oligomers, during formation of the complex amyloid structure. Furthermore, the effects are independent of ATP and the protein unfolding activity of the heat shock protein. As PD affects the older generation in the main, Europe with its demographically ageing population is poised to see an increase in its incidence with a high cost in healthcare. Identification of the molecular culprits and their mode of operation are the first step in development of novel therapeutic strategies.
